Methods and systems for thermally-induced renal neuromodulation

ABSTRACT

Methods and system are provided for thermally-induced renal neuromodulation. Thermally-induced renal neuromodulation may be achieved via direct and/or via indirect application of thermal energy to heat or cool neural fibers that contribute to renal function, or of vascular structures that feed or perfuse the neural fibers. In some embodiments, parameters of the neural fibers, of non-target tissue, or of the thermal energy delivery element, may be monitored via one or more sensors for controlling the thermally-induced neuromodulation. In some embodiments, protective elements may be provided to reduce a degree of thermal damage induced in the non-target tissues. In some embodiments, thermally-induced renal neuromodulation is achieved via delivery of a pulsed thermal therapy.

REFERENCE TO RELATED APPLICATIONS

The present application claims the benefit of the following pendingUnited States patent applications:

(a) U.S. Provisional Patent Application No. 60/880,340, filed on Jan.12, 2007; and

(b) U.S. Provisional Patent Application No. 60/816,999, filed on Jun.28, 2006.

The present application is a continuation-in-part application of each ofthe following co-pending United States patent applications:

(a) U.S. patent application Ser. No. 11/599,723, filed on Nov. 14, 2006;

(b) U.S. patent application Ser. No. 11/504,117, filed on Aug. 14, 2006;and

(c) U.S. patent application Ser. No. 11/189,563, filed on Jul. 25, 2005,which is a continuation-in-part application of U.S. patent application(a) Ser. No. 11/129,765, filed on May 13, 2005, and which claims thebenefit of U.S. Provisional Patent Application Nos. 60/616,254, filed onOct. 5, 2004, and 60/624,793, filed on Nov. 2, 2004; (b) Ser. No.10/900,199 filed on Jul. 28 2004, now U.S. Pat. No. 6,978,174, and (c)Ser. No. 10/408,665, filed on Apr. 8, 2003, now U.S. Pat. No. 7,162,303.

All of these applications are incorporated herein by reference in theirentireties.

INCORPORATION BY REFERENCE

All publications and patent applications mentioned in this specificationare herein incorporated by reference to the same extent as if eachindividual publication or patent application was specifically andindividually indicated to be incorporated by reference.

TECHNICAL FIELD

The present invention relates to methods and systems forneuromodulation. More particularly, the present invention relates tomethods and systems for achieving renal neuromodulation via thermalheating and/or cooling.

BACKGROUND

Congestive heart failure (“CHF”) is a condition typically caused by astructural or functional disorder of the heart and can impair theability of the heart to fill itself or pump a sufficient amount of bloodthroughout a body (e.g., kidneys). It has been established in animalmodels that a heart failure condition can cause abnormally highsympathetic activation of the kidneys, which leads to decreased removalof water from the body, decreased removal of sodium, and increasedsecretion of renin. Increased renin secretion leads to vasoconstrictionof blood vessels supplying the kidneys, which causes decreased renalblood flow. As a result, the reaction of the kidneys to heart failurecan perpetuate a downward spiral of the heart failure condition. Inaddition, the kidneys also play a significant role in the progression ofChronic Renal Failure (“CRF”), End-Stage Renal Disease (“ESRD”),hypertension (pathologically high blood pressure), and other renal orcardio-renal diseases.

Reduction of sympathetic renal nerve activity (e.g., via denervation),can reverse these processes. Ardian, Inc. has developed methods andsystems for treating renal disorders by applying an electric field toneural fibers that contribute to renal function. See, for example,Ardian, Inc.'s co-owned and co-pending U.S. patent application (a) Ser.No. 11/129,765, filed on May 13, 2005, (b) Ser. No. 11/189,563, filed onJul. 25, 2005, and (c) Ser. No. 11/363,867, filed Feb. 27, 2006, all ofwhich are incorporated herein by reference in their entireties. Anelectric field can initiate renal neuromodulation via denervation causedby irreversible electroporation, electrofusion, apoptosis, necrosis,ablation, thermal alteration, alteration of gene expression or anothersuitable modality. The electric field can be delivered from an apparatuspositioned intravascularly, extravascularly, intra-to-extravascularly,or a combination thereof. Additional methods and apparatus for achievingrenal neuromodulation via localized drug delivery (e.g., by a drug pumpor infusion catheter), the use of a stimulation electric field, andother modalities are described, for example, in co-owned U.S. Pat. Nos.7,162,303 and 6,978,174, both of which are incorporated herein byreference in their entireties.

Although these applications provide promising methods and systems,several improvements for enhancing the implementation of these methodsand systems would be desirable.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic view illustrating human renal anatomy.

FIG. 2 is a schematic, isometric detail view illustrating the locationof the renal nerves relative to the renal artery.

FIG. 3A is an isometric view of a system for controllingthermally-induced renal neuromodulation configured in accordance withone embodiment of the disclosure.

FIG. 3B is a schematic side view, partially in section, illustrating anembodiment of an extravascular system for thermally-induced renalneuromodulation.

FIGS. 4A and 4B are schematic diagrams illustrating several types ofthermally-induced renal neuromodulation that may be achieved with thesystems and methods described herein.

FIGS. 5A-5C are schematic side views, partially in section, illustratingan intravascular apparatus for thermally-induced renal neuromodulationconfigured in accordance with an embodiment of the disclosure.

FIGS. 6A and 6B are schematic side views, partially in section,illustrating another embodiment of an intravascular apparatus having oneor more wall-contact electrodes.

FIGS. 7A and 7B are schematic side views, partially in section,illustrating still another embodiment of an intravascular apparatushaving wall-contact electrodes.

FIGS. 8A and 8B are schematic side views, partially in section,illustrating yet another embodiment of an intravascular apparatus havingmultiple wall-contact electrodes.

FIGS. 9A-9F are schematic side views, partially in section, illustratingstill further embodiments of intravascular systems including one or morewall-contact electrodes, as well as optional blood flow occlusionfeatures and/or thermal fluid injection functions.

FIGS. 9G-9N are schematic side views, partially in section, illustratingembodiments of probes for thermally-induced renal neuromodulation.

FIG. 10 is a schematic side view, partially in section, illustrating anexample of an intra-to-extravascular system for thermally-induced renalneuromodulation configured in accordance with an embodiment of thedisclosure.

FIG. 11 is a schematic side view, partially in section, illustrating anembodiment of an apparatus configured for thermally-induced renalneuromodulation via application of thermal energy.

FIG. 12 is a schematic side view, partially in section, illustrating anembodiment of an apparatus for thermally-induced renal neuromodulationcomprising a thermoelectric element suitable for application of thermalenergy to target neural fibers.

FIG. 13 is a schematic side view, partially in section, illustratinganother embodiment of an apparatus for thermally-induced renalneuromodulation comprising a thermoelectric element.

FIGS. 14A and 14B are schematic side views, partially in section,illustrating an embodiment of an apparatus for thermally-induced renalneuromodulation via high-intensity focused ultrasound.

FIG. 15 is a schematic side view, partially in section, illustrating analternative embodiment of the apparatus of FIGS. 14A and 14B.

FIG. 16 is a flow diagram illustrating a method for controlling anenergy delivery process for thermally-induced renal neuromodulation.

FIG. 17 is a block diagram illustrating computing system softwaremodules for controlling thermally-induced renal neuromodulation.

FIG. 18 is a block diagram illustrating a process module suitable to beused in the computer system of FIG. 17.

FIG. 19 is a power vs. time diagram showing an example of a response toperforming the method of FIG. 16.

DETAILED DESCRIPTION A. Overview

The present disclosure provides methods and systems for controllingrenal neuromodulation via thermal heating and/or thermal coolingmechanisms. Many embodiments of such methods and systems may reducerenal sympathetic nerve activity. Thermally-induced neuromodulation maybe achieved by heating or cooling structures associated with renalneural activity via an apparatus positioned proximate to target neuralfibers. For example, such an apparatus can be positioned (a) withinrenal vasculature (i.e., positioned intravascularly), (b)extravascularly, (c) intra-to-extravascularly, or (d) a combinationthereof. Thermally-induced neuromodulation can be achieved by applyingthermal stress to neural structures through either heating or coolingfor influencing or altering these structures. Additionally oralternatively, the thermal neuromodulation can be due to, at least inpart, alteration of vascular structures such as arteries, arterioles,capillaries, or veins that perfuse the target neural fibers orsurrounding tissue.

As used herein, thermal heating mechanisms for neuromodulation includeboth thermal ablation and non-ablative thermal alteration or damage(e.g., via sustained heating or resistive heating). Thermal heatingmechanisms may include raising the temperature of target neural fibersabove a desired threshold to achieve non-ablative thermal alteration, orabove a higher temperature to achieve ablative thermal alteration. Forexample, the target temperature can be above body temperature (e.g.,approximately 37° C.) but less than about 45° C. for non-ablativethermal alteration, or the target temperature can be about 45° C. orhigher for the ablative thermal alteration.

As used herein, thermal cooling mechanisms for neuromodulation includenon-freezing thermal slowing of nerve conduction and/or non-freezingthermal nerve alteration, as well as freezing thermal nerve alteration.Thermal cooling mechanisms may include reducing the temperature oftarget neural fibers below a desired threshold, for example, below thebody temperature of about 37° C. (e.g., below about 20° C.) to achievenon-freezing thermal alteration. Thermal cooling mechanisms also mayinclude reducing the temperature of the target neural fibers below about0° C., e.g., to achieve freezing thermal alteration.

In addition to monitoring or controlling the temperature during thermalneuromodulation, the length of exposure to thermal stimuli may bespecified to affect an extent or degree of efficacy of the thermalneuromodulation. In many embodiments, the length of exposure to thermalstimuli is longer than instantaneous exposure. For example, the durationof exposure can be as short as about 5 seconds, or could be longer, suchas about 30 seconds, or even longer than 2 minutes. In certain specificembodiments, the length of exposure can be less than 10 minutes, butthis should in no way be construed as the upper limit of the exposureperiod. In other embodiments, the exposure can be intermittent orcontinuous to achieve the desired result. Exposure times measured inhours, days, or longer may be utilized to achieve desired thermalneuromodulation.

When conducting neuromodulation via thermal mechanisms, the temperaturethresholds discussed previously may be determined as a function of theduration of exposure to thermal stimuli. Additionally or alternatively,the length of exposure may be determined as a function of the desiredtemperature threshold. These and other parameters may be specified orcalculated to achieve and control desired thermal neuromodulation.

In some embodiments, thermally-induced renal neuromodulation may beachieved by directly and/or indirectly applying thermal cooling orheating energy to the target neural fibers. For example, a chilled orheated fluid can be applied at least proximate to the target neuralfiber, or heated or cooled elements (e.g., a thermoelectric element or aresistive heating element) can be placed in the vicinity of the neuralfibers. In other embodiments, thermally-induced renal neuromodulationmay be achieved via generation and/or application of the thermal energyto the target neural fibers, such as through application of a “thermal”energy field, including, electromagnetic energy, radiofrequency,ultrasound (including high-intensity focused ultrasound), microwave,light energy (including laser, infrared and near-infrared) etc., to thetarget neural fibers. For example, thermally-induced renalneuromodulation may be achieved via delivery of a pulsed or continuousthermal energy field to the target neural fibers. The energy field canbe sufficient magnitude and/or duration to thermally induce theneuromodulation in the target fibers (e.g., to heat or thermally ablateor necrose the fibers). As described herein, additional and/oralternative methods and systems can also be used for thermally-inducedrenal neuromodulation.

When utilizing thermal heating mechanisms for thermal neuromodulation,protective cooling elements, such as conductive or convective coolingelements, optionally may be utilized to protect smooth muscle cells orother non-target tissue from undesired thermal effects during thethermally-induced renal neuromodulation. Likewise, when utilizingthermal cooling mechanisms, protective heating elements, such asconductive or convective heating elements, may be utilized to protectthe non-target tissue. Non-target tissue additionally or alternativelymay be protected by focusing the thermal heating or cooling energy onthe target neural fibers so that the intensity of the thermal energyoutside of the target zone is insufficient to induce undesired thermaleffects in the non-target tissue. When thermal neuromodulation isachieved via thermal energy delivered intravascularly, the non-targettissue may be protected by utilizing blood flow as a conductive and/orconvective heat sink that carries away excess thermal energy (hot orcold). For example, when blood flow is not blocked, the circulatingblood may remove excess thermal energy from the non-target tissue duringthe procedure. The intravascularly-delivered thermal energy may heat orcool target neural fibers located proximate to the vessel to modulatethe target neural fibers while blood flow within the vessel protectsnon-target tissue of the vessel wall from the thermal energy. Forexample, the thermal energy can target neural fibers within theadventitia to necrose or ablate the target fibers, and the blood flowcan protect tissue in the vessel wall.

One drawback of using a continuous, intravascularly-delivered thermalenergy therapy in the presence of blood flow to achieve desiredintravascularly-induced neuromodulation is that the feasible thermalmagnitude (e.g., power) and/or duration of the therapy may be limited orinsufficient. This can be caused by the limited heat capacity of theblood flowing through the blood vessel to remove excess thermal energyfrom the vessel wall to mitigate damage or necrosis to the non-targettissue. Pulsed RF electric fields or other types of pulsed thermalenergy may facilitate greater thermal magnitude (e.g., higher power),longer total duration and/or better controlled intravascular renalneuromodulation therapy compared to a continuous thermal energy therapy.For example, a pulsed thermal therapy may allow for monitoring ofeffects of the therapy on target or non-target tissue during theinterval between the pulses. This monitoring data optionally may be usedin a feedback loop to better control therapy, e.g., to determine whetherto continue or stop treatment, and it may facilitate controlled deliveryof a higher power or longer duration therapy.

Furthermore, the time interval between delivery of thermal energy pulsesmay facilitate additional convective or other cooling of the non-targettissue of the vessel wall compared to applying an equivalent magnitudeor duration of continuous thermal energy. This may occur because bloodflow through the blood vessel may convectively cool (heat) thenon-target tissue of the vessel wall.

When providing a pulsed thermal therapy, this difference in the heattransfer rate between the tissue of the blood vessel wall and therelatively remote target neural fibers may be utilized to ablate,necrose, or otherwise modulate the target neural fibers withoutundesirably affecting the non-target tissue. The pulsed thermal energytherapy may be applied with greater thermal magnitude and/or of longertotal duration (i.e., the cumulative duration of all thermal energypulses within the therapy) than a continuous thermal therapy. Heattransfer from the vessel wall to the blood (or vice versa) during theoff-time or low-energy interval between the thermal energy pulsesfacilitates the greater magnitude with moderated damage to thenon-target tissue. For example, increasing thermal magnitude (e.g.,higher power) may result in an increased rate of heating and,accordingly, a more effective thermal neuromodulation (e.g., ability toaffect nerves further away from the lumen wall).

In addition, or as an alternative, to utilizing the patient's blood as aheat sink to establish the difference in heat transfer rate, a thermalfluid (hot or cold) may be injected, infused, or otherwise deliveredinto the vessel to remove excess thermal energy and protect thenon-target tissues. The thermal fluid may, for example, comprise asaline or other biocompatible fluid that is heated, chilled, or at aroom temperature. The thermal fluid may, for example, be injectedthrough the device or through a guide catheter at a location upstreamfrom an energy delivery element, or at other locations relative to thetissue for which protection is sought. The thermal fluid may be injectedin the presence of blood flow or with the flow temporarily occluded.

Occlusion of flow in combination with thermal fluid delivery mayfacilitate improved control over the heat transfer kinetics in thenon-target tissues. For example, the normal variability in blood flowrate between patients, which would vary the heat transfer capacity ofthe blood flow, may be controlled for by transferring thermal energybetween the vessel wall and a thermal fluid that is delivered at acontrolled rate. Use of injected thermal fluids to remove excess thermalenergy from non-target tissues to relatively protect the non-targettissues during therapeutic treatment of target tissues may be utilizedin body lumens other than blood vessels.

In some embodiments, methods and apparatuses for real-time monitoring ofan extent or degree of neuromodulation or denervation (e.g., an extentor degree of thermal alteration) in tissue innervated by the targetneural fibers and/or of thermal damage in the non-target tissue may beprovided. Likewise, real-time monitoring of the thermal energy deliveryelement may be provided. Such methods and apparatuses may, for example,comprise a thermocouple or other temperature sensor for measuring thetemperature of the monitored tissue or of the thermal energy deliveryelement. Other parameters that can be measured include the power, totalenergy delivered, nerve activity or impedance. Monitoring data may beused for feedback control of the thermal therapy. For example,intravascularly-delivered thermal therapy may be monitored andcontrolled by acquiring temperature or impedance measurements along thewall of the vessel in the vicinity of the treatment zone, and/or bylimiting the power or duration of the therapy.

To better understand the structures of several embodiments of devicesdescribed below, as well as the methods of using such devices forthermally-induced renal neuromodulation, a description of the renalanatomy in humans is provided.

B. Renal Anatomy Summary

As shown in FIG. 1, the human renal anatomy includes the kidneys K,which are supplied with oxygenated blood by the renal arteries RA. Therenal arteries are connected to the heart via the abdominal aorta AA.Deoxygenated blood flows from the kidneys to the heart via the renalveins RV and the inferior vena cava IVC.

FIG. 2 illustrates a portion of the renal anatomy in greater detail.More specifically, the renal anatomy also includes renal nerves RNextending longitudinally along the lengthwise dimension L of renalartery RA. The renal nerves RN, for example, are generally within theadventitia of the artery. The renal artery RA has smooth muscle cellsSMC that surround the arterial circumference and spiral around theangular axis θ of the artery. The smooth muscle cells of the renalartery accordingly have a lengthwise or longer dimension extendingtransverse (i.e., non-parallel) to the lengthwise dimension of the renalartery. The misalignment of the lengthwise dimensions of the renalnerves and the smooth muscle cells is defined as “cellularmisalignment.”

C. Embodiments of Systems and Methods for Thermally-Induced RenalNeuromodulation

FIGS. 3A-19 illustrate examples of systems and methods forthermally-induced renal neuromodulation. FIG. 3A, for example, is anisometric view of a system 100 for controlling thermally-induced renalneuromodulation of a patient 101 configured in accordance with anembodiment of the disclosure. The system 100 can include a processor114, a field generator 110 electrically connected to the processor 114,and a probe 104 operatively coupled to the field generator 110. In theillustrated embodiment, a cable 112 electrically connects the probe 104to the field generator 110. In other embodiments, the processor 114, theprobe 104, and/or the field generator 110 can be connected wirelesslyvia, for example, radio frequency signals.

The processor 114 can be any general purpose, programmable digitalcomputing device including, for example, a personal computer, aProgrammable Logic Controller, a Distributed Control System, or othercomputing device. The processor 114 can include a central processingunit (CPU), random access memory (RAM), non-volatile secondary storage(e.g., a hard drive, a floppy drive, and a CD-ROM drive), and networkinterfaces (e.g., a wired or wireless Ethernet card and a digital and/oranalog input/output card). Program code and data can be loaded into theRAM from the non-volatile secondary storage and provided to the CPU forexecution. The CPU can generate results for display, output, transmit,or storage.

The field generator 110 can generate electrical, radiofrequency,ultrasonic (including high intensity focused ultrasound), microwave,laser or other types of signals with desired parameters sufficient tothermally or otherwise induce renal neuromodulation in target neuralfibers. For example, the field generator 110 can generate an electricalsignal having a desired frequency, amplitude, and power level, and thecable 112 can transmit the generated signal to the probe 104. Theprocessor 114 is in communication with the field generator 110 tocontrol the power output of the field generator 110 for providing thedesired amount of energy to the target neural structures. In theillustrated embodiment, the field generator 110 is located external tothe patient 101. In other embodiments, however, the field generator 110may be positioned internally within the patient.

The probe 104 can be a laparoscopic probe, a percutaneous probe, anintravascular catheter, or another suitable device configured forinsertion in proximity to a track of a renal neural supply along and/orin the renal artery, renal vein, hilum, and/or Gerota's fascia under CT,radiographic, or another suitable guidance modality. The probe 104 caninclude at least one electrode 108 for delivery of a thermal energyfield therapy and an electrical connector 106 coupled to the fieldgenerator 110 via the cable 112 for delivering a thermal energy field tothe electrode 108. In some embodiments, the probe 104 can include anintegrated cable (not shown) for delivering a thermal energy field tothe electrode 108, and the electrical connector 106 can be omitted. Inthe illustrated embodiment, the probe 104 is a percutaneous probeconfigured to be percutaneously advanced into proximity of, for example,an anatomical target 102 (e.g., a renal artery or renal vein) of thepatient 101 as described in more detail below with reference to FIG. 3B.In other embodiments, the probe 104 can be an implantable device.

The electrode(s) 108 can be individual electrodes that are electricallyindependent of each other, a segmented electrode with commonly connectedcontacts, or a continuous electrode. A segmented electrode can, forexample, be formed by providing a slotted tube fitted onto theelectrode, or by electrically connecting a series of individualelectrodes. Individual electrodes or groups of electrodes 108 can beconfigured to provide a bipolar signal. The electrodes 108 can bedynamically assignable to facilitate monopolar and/or bipolar energydelivery between any of the electrodes and/or between any of theelectrodes and a remote electrode. The remote electrode may, forexample, be attached externally to the patient's skin (e.g., to thepatient's leg or flank).

The probe 104 can also include at least one sensor (not shown) formeasuring a physiological parameter of the patient 101. For example, theprobe 104 can include a temperature sensor, an impedance sensor, anultrasound sensor, and/or other types of sensors. The sensor can measurethe physiological parameter (e.g., a temperature) and transmit themeasured physiological parameter to the processor 114 for processing.

Optionally, the system 100 can also include an input device 118, anoutput device 120, and/or a control panel 122 operatively coupled to theprocessor 114. The input device 118 can include a keyboard, a mouse, atouch screen, a push button, a switch, a potentiometer, and any otherdevices suitable for accepting user input. The output device 120 caninclude a display screen, a printer, a medium reader, an audio device,and any other devices suitable for providing user feedback. The controlpanel 122 can include indicator lights, numerical displays, and audiodevices. In the embodiment shown in FIG. 3A, a rack 124 with wheels 126carries the processor 114, the field generator 110, the input device118, and the output device 120 for portability. In another embodiment,the various components can be incorporated into a single enclosure(e.g., the field generator 110) for portably mounting on, for example,an IV stand, an IV pole, an instrument stand, an infusion stand, and/orother supporting structures. In further embodiments, the variouscomponents can be fixedly installed.

In operation, an operator can place the probe 104 at least proximate toa wall of a body lumen of the patient 101, for example, the renal arteryor renal vein, and then deliver energy to the probe 104 to achievethermal renal neuromodulation as described in more detail below. FIGS.4A and 4B, for example, illustrate the various types of thermalneuromodulation that may be achieved with the systems and methodsdescribed herein. FIGS. 4A and 4B are provided only for the sake ofillustration and should in no way be construed as limiting.

FIG. 4A illustrates thermal neuromodulation due to heat exposure. Asshown, exposure to heat in excess of a body temperature of about 37° C.,but below a temperature of about 45° C., may induce thermal alterationvia moderate heating of the target neural fibers or of vascularstructures that perfuse the target fibers. In cases where vascularstructures are affected, the target neural fibers are denied perfusionresulting in necrosis of the neural tissue. For example, this may inducenon-ablative thermal alteration in the fibers or structures. Exposure toheat above a temperature of about 45° C., or above about 60° C., mayinduce thermal alteration via substantial heating of the fibers orstructures. For example, such higher temperatures may thermally ablatethe target neural fibers or the vascular structures. In some patients,it may be desirable to achieve temperatures that thermally ablate thetarget neural fibers or the vascular structures, but that are less thanabout 90° C., or less than about 85° C., or less than about 80° C.,and/or less than about 75° C. Regardless of the type of heat exposureutilized to induce the thermal neuromodulation, a reduction in renalsympathetic nerve activity (“RSNA”) is expected.

Referring to FIG. 4B, thermal cooling for neuromodulation includesnon-freezing thermal slowing of nerve conduction and/or nervealteration, as well as freezing thermal nerve alteration. Non-freezingthermal cooling may include reducing the temperature of the targetneural fibers or of the vascular structures that feed the fibers totemperatures below the body temperature of about 37° C., or below about20° C., but above the freezing temperature of about 0° C. Thisnon-freezing thermal cooling may either slow nerve conduction or maycause neural alteration. Slowed nerve conduction may use continuous orintermittent cooling of the target neural fibers to sustain the desiredthermal neuromodulation, while neural alteration may require only adiscrete treatment to achieve sustained thermal neuromodulation. Thermalcooling for neuromodulation also may include freezing thermal nervealteration by reducing the temperature of the target neural fibers or ofthe vascular structures that feed the fibers to temperatures below thefreezing point of about 0° C. Regardless of the type of cold exposureutilized to induce the thermal neuromodulation (freezing ornon-freezing), a reduction in RSNA is expected.

Referring back to FIG. 3A, the operator and/or the processor 114 canmonitor and control the energy delivery process. As described above, theprobe 104 can include sensors that measure physiological parameters ofthe patient 101. The probe 104 can transmit the measured parameters tothe processor 114 via the cable 112 or wirelessly. The processor 114 canprocess and analyze the received parameters and display the parametersin appropriate units on the output device 120. The processor 114 cancause the system to sound an alarm if the received parameters exceedpreset thresholds and signal any alarms using either the output device120 and/or the control panel 122. The processor 114 can also analyze andprocess parameter measurement data, for either a single parameter ormultiple parameters in combination, and can compare the data againststored, non-empirical data to identify any patterns that may warrantcloser attention. The processor 114 can also store the receivedparameters and data patterns in a database for later retrieval. Inaddition, the processor 114 can modulate the power output of the fieldgenerator 110 based on the received parameters and/or input receivedfrom the operator via the input device 118 as described in more detailbelow with reference to FIGS. 16-19.

In FIG. 3B, the probe 104 has been advanced through a percutaneousaccess site P into proximity with the renal artery RA. The probe 104pierces the Gerota's fascia F of the patient 101, and the electrodes 108are advanced into position through the probe 104 and along the annularspace between the artery and fascia. Once properly positioned, thetarget neural fibers can be heated via a pulsed or continuous electricfield delivered across the electrode(s) 108. In FIG. 3B, for example,the electrode(s) 108 comprise a bipolar electrode pair that can generatethermal energy field 109. Such heating can ablate or cause non-ablativethermal alteration to the target neural fibers to at least partiallydenervate the kidney innervated by the target neural fibers. The energyfield also can induce reversible or irreversible electroporation in thetarget neural fibers which can compliment the thermal alteration inducedin the neural fibers. After treatment, the probe 104 can be removed fromthe patient to conclude the procedure.

FIGS. 5A-9, 14, and 15 illustrate several embodiments of intravascularsystems and associated methods for thermally-induced renalneuromodulation. It will be appreciated that the electrode(s) in each ofthe following embodiments can be connected to a generator (e.g., thefield generator 110) even through the generator is not explicitly shownor described below.

FIGS. 5A and 5B, for example, are schematic side views illustrating anintravascular apparatus 300 for thermally-induced renal neuromodulation.The apparatus 300 can include a catheter 302 having an optionalpositioning element 304, shaft electrodes 306 a and 306 b disposed alongthe shaft of the catheter 302, and optional radiopaque markers 308disposed along the shaft of the catheter 302 in the region of thepositioning element 304. The positioning element 304 can be a balloon,an expandable wire basket, other mechanical expanders, or anothersuitable device for holding the electrodes 306 a-b relative to thevessel and/or the nerves. The electrodes 306 a-b can be arranged suchthat the electrode 306 a is near a proximal end of the positioningelement 304 and the electrode 306 b is near the distal end of thepositioning element 304. The electrodes 306 a-b are electrically coupledto the field generator 110 (FIG. 3A) for delivering energy to the targetneural fibers. In other embodiments, one or more of the electrodes 306a-b can comprise Peltier electrodes for heating or cooling the targetneural fibers to modulate the fibers.

The positioning element 304 optionally can position or otherwise drivethe electrodes 306 a-b into contact with the lumen wall. For example,when the positioning element 304 is an inflatable balloon as shown inFIG. 5A, the balloon can serve as both a centering and/or expansionelement for the expandable electrode element(s) 306 a-b, and as animpedance-altering electrical insulator for directing an energy fielddelivered via the electrodes 306 a-b into or across the vessel wall formodulation of target neural fibers. The electrical insulation providedby the positioning element 304 can reduce the magnitude of appliedenergy or other parameters of the energy field necessary to achieve thedesired modulation of the target fibers, which can include partial orfull denervation of tissue containing the target fibers. Applicants havepreviously described use of a suitable impedance-altering element inco-pending U.S. patent application Ser. No. 11/266,993, filed Nov. 4,2005, which is incorporated herein by reference in its entirety.

Furthermore, the positioning element 304 optionally may be utilized as acooling element and/or a heating element. For example, the positioningelement 304 may be inflated with a chilled fluid that serves as a heatsink for removing heat from tissue that contacts the element.Conversely, the positioning element 304 optionally may be a heatingelement by inflating it with a warmed fluid that heats tissue in contactwith the element. The thermal fluid optionally may be circulated and/orexchanged within the positioning element 304 to facilitate moreefficient conductive and/or convective heat transfer. Thermal fluidsalso may be used to achieve thermal neuromodulation via thermal coolingor heating mechanisms, as described in greater detail herein below.

The positioning element 304 (or any other portion of the apparatus 300)additionally or alternatively may comprise one or more sensors formonitoring the process. In one embodiment, the positioning element 304has a wall-contact thermocouple 310 (FIG. 5A) for monitoring thetemperature or other parameters of the target tissue, the non-targettissue, the electrodes, the positioning element and/or any other portionof the apparatus 300. Alternatively, electrodes 306 a and/or 306 b canhave one or more thermocouples built into them.

The electrodes 306 a-b of the intravascular embodiment shown in FIGS. 5Aand 5B can be individual electrodes (i.e., independent contacts), asegmented electrode with commonly connected contacts, or a singlecontinuous electrode. Furthermore, the electrodes 306 a-b can also beconfigured to provide a bipolar signal, or the electrodes 306 a-b can beused together or individually in conjunction with a separate patientground pad for monopolar use. The electrodes 306 a-b can be attached tothe positioning element 304 such that they contact the wall of theartery upon expansion of the positioning elements 304. The electrodes306 a-b can, for example, be affixed to the inside surface, outsidesurface, or at least partially embedded within the wall of thepositioning element 304. FIG. 5C, described hereinafter, illustrates oneexample of wall-contact electrodes, while FIGS. 6-9 illustratealternative wall-contact electrodes.

As shown in FIG. 5A, the catheter 302 can be delivered to a treatmentsite within the renal artery RA as shown, or it may be delivered to arenal vein or to any other vessel in proximity to neural tissuecontributing to renal function, in a low profile delivery configurationthrough a guide catheter or other device. Alternatively, catheters maybe positioned in multiple vessels for thermal renal neuromodulation,e.g., within both the renal artery and the renal vein. Techniques forpulsed electric field renal neuromodulation in multiple vessels havebeen described previously, for example, in co-pending U.S. patentapplication Ser. No. 11/451,728, filed Jul. 12, 2006, which isincorporated herein by reference in its entirety.

Once the positioning element 304 is at a desired location within therenal vasculature, it can be expanded into contact with an interior wallof the vessel. A thermal energy field then may be delivered via theelectrodes 306 a-b across the wall of the artery. The field thermallymodulates the activity along neural fibers that contribute to renalfunction via heating. In several embodiments, the thermal modulation atleast partially denervates the kidney innervated by the neural fibersvia heating. This may be achieved, for example, via thermal ablation ornon-ablative alteration of the target neural fibers.

In the embodiment shown in FIG. 5A, the positioning element 304 is aninflatable balloon that can preferentially direct the energy field asdiscussed above. In the embodiment illustrated in FIG. 5B, thepositioning element 304 comprises an expandable wire basket thatsubstantially centers the electrodes 306 a-b within the vessel withoutblocking blood flow through the vessel. During delivery of the thermalenergy field (or of other thermal energy), the blood can act as a heatsink for conductive and/or convective heat transfer to remove excessthermal energy from the non-target tissue. This protects the non-targettissue from undesired thermal effects. This effect may be enhanced whenblood flow is not blocked during energy delivery, such as in theembodiment shown in FIG. 5B.

Using the patient's blood as a heat sink is expected to facilitatedelivery of longer or greater magnitude thermal treatments with reducedrisk of undesired effects to the non-target tissue, which may enhancethe efficacy of the treatment at the target neural fibers. Although theembodiment shown in FIG. 5B includes a positioning element 304 forcentering the electrodes 306 a-b without blocking flow, it should beunderstood that the positioning element 304 may be eliminated and/orthat the electrodes 306 a-b may be attached to the positioning element304 such that they are not centered in the vessel upon expansion of thecentering element. In such embodiments, the patient's blood may stillmitigate excess thermal heating or cooling to protect non-targettissues.

One drawback of using a continuous, intravascularly-delivered thermalenergy therapy in the presence of blood flow to achieve desiredintravascularly-induced neuromodulation is that the feasible thermalmagnitude (e.g., power) and/or duration of the therapy may be limited orinsufficient. This can occur because the capacity of the blood to removeheat is limited, and thus the blood flowing through the blood vessel maynot remove enough excess thermal energy from the vessel wall to mitigateor avoid undesirable effect in the non-target tissue. Use of a pulsedthermal energy therapy, such as a pulsed thermal RF electric field, mayfacilitate greater thermal magnitude (e.g., higher power), longer totalduration, and/or better controlled intravascular renal neuromodulationtherapy compared to a continuous thermal energy therapy. For example,the effects of the therapy on target or non-target tissue may bemonitored during the intervals between the pulses. This monitoring dataoptionally may be used in a feedback loop to better control the therapy,e.g., to determine whether to continue or stop treatment, and it mayfacilitate controlled delivery of a higher power or longer durationtherapy.

Furthermore, the off-time or low-energy intervals between thermal energypulses may facilitate additional convective or other cooling of thenon-target tissue of the vessel wall compared to use of a continuousthermal therapy of equivalent magnitude or duration. This can occurbecause blood flow through the blood vessel can convectively cool (heat)the non-target tissue of the vessel wall faster than the target neuralfibers positioned outside of the vessel wall.

When providing a pulsed thermal therapy, the difference in heat transferrates between tissue of the blood vessel wall and the relatively remotetarget neural fibers may be utilized to ablate, necrose, or otherwisemodulate the target neural fibers without producing undesirable effectsin the non-target tissue. As a result, the pulsed thermal energy therapymay be applied with greater thermal magnitude and/or of longer totalduration (i.e., the cumulative duration of all thermal energy pulses)compared to a continuous thermal therapy. The higher heat transfer rateat the vessel wall during the intervals between the thermal energypulses facilitates the greater magnitude/longer duration delivery.

In addition or as an alternative to utilizing the patient's blood as aheat sink to create a difference in the heat transfer rate, a thermalfluid (hot or cold) may be injected, infused or otherwise delivered intothe vessel to remove excess thermal energy and protect the non-targettissues. The thermal fluid may, for example, comprise saline or anotherbiocompatible fluid that is heated, chilled or at room temperature. Thethermal fluid may, for example, be injected through the device orthrough a guide catheter at a location upstream from an energy deliveryelement, or at other locations relative to the tissue for whichprotection is sought. The thermal fluid may be injected in the presenceof blood flow or with the blood flow temporarily occluded.

In several embodiments, the occlusion of the blood flow in combinationwith thermal fluid delivery may facilitate good control over the heattransfer kinetics. For example, the normal variability in blood flowrate between patients, which would vary the heat transfer capacity ofthe blood flow, may be controlled for by transferring thermal energybetween the vessel wall and a thermal fluid that is delivered at acontrolled rate. Furthermore, this method of using an injected thermalfluid to remove excess thermal energy from non-target tissues in orderto protect the non-target tissues during therapeutic treatment of targettissues may be utilized in body lumens other than blood vessels.

One or more sensors, such as the thermocouple 310 of FIG. 5A, can beused to monitor the temperature(s) or other parameter(s) at theelectrodes 306 a-b, the wall of the vessel and/or at other desiredlocations along the apparatus or the patient's anatomy. The thermalneuromodulation may be controlled using the measured parameter(s) asfeedback. This feedback may be used, for example, to maintain theparameter(s) below a desired threshold. For example, the parameter(s)may be maintained below a threshold that may cause undesired effects inthe non-target tissues. With blood flowing through the vessel, morethermal energy may be carried away, which may allow for higher energytreatments than when blood flow is blocked in the vessel.

As discussed previously, when utilizing intravascular apparatus toachieve thermal neuromodulation, in addition or as an alternative tocentral positioning of the electrode(s) within a blood vessel, theelectrode(s) optionally may be configured to contact an internal wall ofthe blood vessel. Wall-contact electrode(s) may facilitate moreefficient transfer of a thermal energy field across the vessel wall totarget neural fibers, as compared to centrally-positioned electrode(s).In some embodiments, the wall-contact electrode(s) may be delivered tothe vessel treatment site in a reduced profile configuration, thenexpanded in vivo to a deployed configuration wherein the electrode(s)contact the vessel wall. In some embodiments, expansion of theelectrode(s) is at least partially reversible to facilitate retrieval ofthe electrode(s) from the patient's vessel.

FIG. 5C, for example, is a schematic side view illustrating anembodiment of an apparatus 400 having one or more wall-contactelectrodes 306 c. One or more struts of the expandable basketpositioning element 304 can include a conductive material that isinsulated in regions other than along segments that contact the vesselwall and form electrode(s) 306 c. The electrode(s) 306 c can be used ineither a bipolar or a monopolar configuration. Furthermore, theelectrode(s) 306 c can include one or more sensors (not shown) formonitoring and/or controlling the effects of the thermal energydelivery. The sensors, for example, can be thermocouples, impedancesensors, temperature sensors, etc.

FIGS. 6A and 6B are schematic side views illustrating another embodimentof an intravascular apparatus 500 having electrodes configured tocontact the interior wall of a vessel. The apparatus 500 of FIGS. 6A and6B differs from the apparatus 300 of FIGS. 5A and 5B in that theproximal electrode 306 a of FIGS. 5A and 5B has been replaced with awall-contact electrode 306 a′. The wall-contact electrode 306 a′includes a proximal connector 312 a that connects the electrode 306 a′to the shaft of the catheter 302 and is electrically coupled to thefield generator (not shown). The apparatus 500 also has a plurality ofextensions 314 a that extend from the proximal connector 312 a and atleast partially extend over a surface of the positioning element 304.The extensions 314 a optionally may be selectively insulated such thatonly a selective portion of the extensions 314 a (e.g., the distal tipsof the extensions) are electrically active. The electrode 306 a′ and orthe connector 312 a optionally may be fabricated from a slotted tube,such as a stainless steel or shape-memory (e.g., NiTi) slotted tube.Furthermore, all or a portion of the electrode may be gold-plated toimprove radiopacity and/or conductivity.

As shown in FIG. 6A, the catheter 302 may be delivered over a guidewireG to a treatment site within the patient's vessel with the electrode 306a′ positioned in a reduced profile configuration. The catheter 302optionally may be delivered through a guide catheter 303 to facilitatesuch reduced profile delivery of the wall-contact electrode 306 a′. Whenpositioned as desired at a treatment site, the electrode 306 a′ may beexpanded into contact with the vessel wall by expanding the positioningelement 304 (as shown in FIG. 6B). A thermal bipolar electric field thenmay be delivered across the vessel wall and between the electrodes 306a′ and 306 b to induce thermal neuromodulation, as discussed previously.Alternatively 306 a′ or 306 b could comprise a monopolar electrode,wherein the return electrode (not shown) is placed on an externalsurface of the patient. The optional positioning element 304 may alterimpedance within the blood vessel and more efficiently route theelectrical energy across the vessel wall to the target neural fibers.

After terminating the electric field, the electrode 306 a′ may bereturned to a reduced profile and the apparatus 500 may be removed fromthe patient or repositioned in the vessel. For example, the positioningelement 304 may be collapsed (e.g., deflated), and the electrode 306 a′may be contracted by withdrawing the catheter 302 within the guidecatheter 303. Alternatively, the electrode 306 a′ may be fabricated froma shape-memory material biased to the collapsed configuration, such thatthe electrode self-collapses upon collapse of the positioning element304.

Although the electrode 306 a′ shown in FIGS. 6A and 6B is expanded intocontact with the vessel wall, it should be understood that the electrode306 a′ alternatively may be fabricated from a self-expanding materialbiased such that the electrode 306 a′ self-expands into contact with thevessel wall upon positioning of the electrode 306 a′ distal of the guidecatheter 303. A self-expanding embodiment of the electrode 306 a′ mayobviate a need for the positioning element 304 and/or may facilitatemaintenance of blood flow through the blood vessel during delivery of anelectric field via the electrode. After delivery of the electric field,the self-expanding electrode 306 a′ may be returned to a reduced profileto facilitate removal of the apparatus 300 from the patient bywithdrawing the catheter 302 within the guide catheter 303.

FIGS. 7A and 7B are schematic side views illustrating still anotherembodiment of an apparatus 600 for delivering a field using awall-contact electrode 306 a″. FIG. 7A shows the electrode 306 a″ in areduced profile configuration, and FIG. 7B shows the electrode 306 a″ inan expanded configuration in which the conductive portions of theelectrode 306 a″ contact the vessel wall. As an alternative to theproximal connector 312 a of the electrode 306 a′ of FIGS. 6A and 6B, theelectrode 306 a″ of FIGS. 7A and 7B includes a distal connector 316 afor coupling the electrode 306 a″ to the shaft of the catheter 302 onthe distal side of the positioning element 304. The distal connector 316a enables the electrode 306 a″ to extend over the entirety of thepositioning element 304 and can facilitate contraction of the electrode306 a″ after thermal neuromodulation. For example, the electrode 306 a″can be contracted by proximally retracting the guide catheter303relative to the catheter 302 during or after contraction of thepositioning element 304. Alternatively, the wires at the proximal end ofthe apparatus can be proximally retracted to contract the electrode 306a″.

FIGS. 8A and 8B are schematic side views illustrating yet anotherembodiment of an apparatus 700 for thermally-induced neuromodulation.The apparatus 700 of FIGS. 8A and 8B includes the proximal electrode 306a′ of FIGS. 6A and 6B, and a distal wall-contact electrode 306 b′. Theapparatus 700 also includes proximal and distal positioning elements 304a and 304 b, respectively, for expanding the proximal and distalwall-contact electrodes 306 a′ and 306 b′, respectively, into contactwith the vessel wall. The embodiment shown in FIG. 8B includes only asingle positioning element 304, but the distal wall-contact electrode306 b′ is proximal facing and positioned over the distal portion of thepositioning element 304 to facilitate expansion of the distal electrode306 b′. In the embodiment illustrated in FIG. 8B, the extensions of theproximal 306 a′ and distal electrodes 306 b′ optionally may be connectedalong non-conductive connectors 318 to facilitate collapse and retrievalof the electrodes post-treatment.

A bipolar electric field may be delivered between the proximal anddistal wall-contact electrodes 306 a′ and 306 b′, or a monopolarelectric field may be delivered between the proximal electrode 306 a′and/or distal electrode 306 b′ and an external ground. Having both theproximal and distal electrodes 306 a′ and 306 b′ in contact with thewall of the vessel may facilitate more efficient energy transfer acrossthe wall during delivery of a thermal energy field, as compared tohaving one or both of the proximal and distal electrodes 306 a′ and 306b′ centered within the vessel.

FIGS. 9A-9N are schematic side views illustrating additional embodimentsof intravascular systems including one or more wall-contact electrodes,blood flow occlusion features, and/or thermal fluid injection functions.The embodiments described below with reference to FIGS. 9A-9N aredescribed as monopolar devices, but it should be understood that any (orall) of the embodiments may be configured or operated as bipolardevices. Furthermore, although blood flow occlusion and thermal fluidinjection are described in combination with wall-contact electrode(s),it should be understood that such occlusion and injection features maybe provided in combination with electrode(s) that do not contact thevessel wall.

As discussed previously, in addition or as an alternative to utilizingthe patient's blood as a heat sink to create different heat transferrates between target neural fibers and non-target tissue of the wall ofthe vessel within which thermal energy is delivered, a thermal fluid(hot or cold) may be injected, infused or otherwise delivered into thevessel. The thermal fluid may further remove excess thermal energy andprotect the non-target tissues. When delivering thermal therapy viaheating, the thermal fluid may, for example, comprise chilled or roomtemperature saline (e.g., saline at a temperature lower than thetemperature of the vessel wall during the therapy delivery). The thermalfluid may be injected through the device catheter or through a guidecatheter at a location upstream from an energy delivery element, or atother locations relative to the tissue for which protection is sought.The thermal fluid may be injected in the presence of blood flow or withblood flow temporarily occluded. The occlusion of blood flow incombination with thermal fluid delivery may facilitate good control overthe heat transfer kinetics along the non-target tissues, as well asinjection of fluid from a downstream location.

FIGS. 9A and 9B illustrate an apparatus 800 including a catheter 802having a positioning element 804 that can be used to position theapparatus within the vessel and/or to occlude blood flow. Thepositioning element 804, for example, can be an inflatable balloon. Theapparatus 800 can further include one or more active monopolarelectrodes 810 located proximally from the positioning element 804 suchthat inflation of the positioning element 804 blocks blood flowdownstream of the electrode assembly 806. The electrode assembly 806includes multiple extensions 814, and it should be understood that anydesired number of extensions may be provided, including a singleextension. The monopolar electrode(s) 810 are utilized in combinationwith a remote electrode, such as a ground pad, positioned external tothe patient. The apparatus 800 can also include an infusion port 805between the positioning element 804 and the electrode assembly 806.

As shown in FIG. 9A, the catheter 802 can be advanced within the renalartery RA in a reduced profile delivery configuration. Referring to FIG.9B, once properly positioned at the treatment site, the electrodeassembly 806 can be actively expanded, or it may self-expand by removinga sheath, the guide catheter 803, or another type of restraint from theelectrode(s) 810. The expanded electrode assembly 806 contacts thevessel wall. The positioning element 804 can be expanded (before,during, or after expansion of the electrode assembly 806) to properlyposition the electrode assembly 806 within the vessel and/or to occludeblood flow within the renal artery RA downstream of the electrodeassembly 806. A monopolar electric field may be delivered between theactive electrode(s) 810 and the external ground. Alternatively, abiopolar electric field can be generated between any two electrodes 810.The electric field may, for example, comprise a pulsed or continuous RFelectric field that thermally induces neuromodulation (e.g., necrosis orablation) in the target neural fibers. The thermal therapy may bemonitored and controlled, for example, via data collected withthermocouples, impedance sensors, or other sensors, which may beincorporated into electrode(s) 810.

To increase the power that may be delivered or the duration of thethermal treatment without undesirably affecting non-target tissue, athermal fluid infusate I can be injected through injection port 805 ofthe catheter 802 to cool the non-target tissue. This is expected tomitigate undesired effects in the non-target tissue. The infusate I, forexample, can include chilled saline that removes excess thermal energyfrom the wall of the vessel during thermal therapy.

Convective or other heat transfer between the non-target vessel walltissue and the infusate I may facilitate cooling (or heating) of thevessel wall at a faster rate than cooling (or heating) occurs at thetarget neural fibers. This difference in the heat transfer rates betweenthe wall of the vessel and the target neural fibers may be utilized tomodulate the neural fibers. Furthermore, when utilizing a pulsed thermaltherapy, the accelerated heat transfer at the wall relative to theneural fibers may allow for relatively higher energy or longer durationtherapies (as compared to continuous thermal therapies). Also, theinterval between pulses may be used to monitor and/or control effects ofthe therapy.

FIG. 9C is a schematic side view illustrating another embodiment of anapparatus 820 including wall-contact electrodes 810, flow occlusion, andthermal fluid injection. In the embodiment shown in FIG. 9C, anocclusion element 804 is coupled to the guide wire G, which may comprisean inflation lumen, and the infusate I is delivered through a distaloutlet of the catheter 802. The occlusion element 804 alternatively maybe coupled to a separate catheter or sheath (not shown) rather than tothe guide wire G. Also, the infusate I may, for example, be deliveredthrough the guide wire lumen or through an additional lumen or annulusof the catheter 802. FIG. 9D illustrates another embodiment of anapparatus 830 where occlusion element 804 is positioned proximal orupstream of the electrode assembly 806, and the infusate I is deliveredat a position distal of the occlusion element 804 but proximal of theelectrode assembly 806.

FIG. 9E is a schematic side view illustrating yet another embodiment ofan apparatus 840 with occlusion elements 804 (two are shown as occlusionelements 804 a and 804 b) positioned both proximal and distal of theelectrode assembly 806. In addition to having a first injection port 805a, the catheter 803 includes an aspiration port 805 b. Separate lumenscan extend through the catheter for injection and aspiration of theinfusate I via the injection ports 805 a and 805 b. Providing bothinjection and aspiration of the infusate facilitates good control overthe flow dynamics of the infusate, and thereby the heat transferkinetics of the infusate I. For example, providing aspiration andinjection at the same rate can provide consistent heat transfer kineticsbetween the vessel and the electrode(s) 806.

FIG. 9F illustrates still yet another embodiment of an apparatus 850having a catheter 852 including a wall-contact electrode 856 that can bemoved into contact with the vessel wall via an elongated member 857. Inthis embodiment, the elongated member 857 is distally connected to thecatheter 852 in the vicinity of the electrode 856. The elongated member857 may be configured for self or mechanical expansion, or it may extendthrough a port 805 of the catheter 852 and through a lumen of thecatheter to a proximal location for manipulation by a medicalpractitioner. The proximal section of the elongated member 857 may beadvanced relative to the catheter 852 by the medical practitioner suchthat the member assumes the illustrated curved profile.

Upon expansion of the elongated member, the catheter 852 is deflectedsuch that the electrode 856 coupled to the catheter shaft contacts thevessel wall. Optionally, the positioning element 804 may be expanded tofacilitate positioning of the electrode 856 via the elongated member 857and/or to block flow through the vessel. The positioning element 804 canbe coupled to the guide or delivery catheter 803. Infusate I optionallymay be delivered through the catheter 852 as shown.

FIGS. 9G-9N are partially schematic side views illustrating anembodiment of a probe or catheter 900 including a shaped orself-expanding or mechanically-activated electrode suitable for use inthe system 100 of FIGS. 3A and 3B. FIG. 9G, for example, illustrates theprobe or catheter 900 in a reduced profile configuration for delivery tothe treatment site, and FIG. 9H illustrates a portion of the probe 900in an expanded or uncompressed state. Referring to FIGS. 9G and 9Htogether, the probe 900 can include a shaft 904, an electrode 906, anintermediate portion or section 908 between the shaft 904 and theelectrode 906, and a guide catheter or sheath 910 (e.g., a 5 Frenchguide catheter) covering and releasably carrying the shaft 904 and theintermediate portion 908. The intermediate portion 908 can rest withinthe sheath 910 in a compressed state (i.e., the curved or shaped regionis substantially flattened or otherwise straightened by the inner wallof the sheath 910) during delivery to the treatment site (FIG. 9G). Whenthe sheath 910 is retracted, the intermediate portion 908 will expand toits unconstrained arched or curved shape (FIG. 9H). The curved or shapedprofile of the intermediate portion 908 facilitates contact between theelectrode 906 and the corresponding vessel wall. This process isdescribed in greater detail below with reference to FIG. 9J.

As best seen in the reduced profiled configuration of FIG. 9G, the shaft904 and the intermediate portion 908 can optionally have an internalspace 912 (not shown), and the probe 900 can further include wires 112(identified individually as 112 a and 112 b) coupled to the intermediateportion 908. The wires 112 a-b electrically couple the electrode 906 tothe field generator 110 and may be comprised of thermocouple wires. Asdiscussed in more detail below, the electrode 906 can deliver anelectric field supplied by the field generator 110 via the wires 112 tothe wall of the corresponding body lumen.

Referring back to FIGS. 9G and 9H together, the shaft 904 can be agenerally cylindrical tube constructed from one or more biocompatiblematerials (e.g., plastic, metals, alloys, and ceramics). The shaft 904can also include a more flexible region or section 904 a at a distalportion of the shaft 904 and configured to allow the probe 900 to flexor contort during use. For example, the flexible region 904 a can allowthe probe 900 to make the relatively sharp turn from the aorta to therenal artery during delivery of the electrode 906 to the treatment site.In one embodiment, the flexible region 904 a can include a braided shaftwithout the support of a hypotube or other support structure which maybe incorporated into the shaft 904. As shown in FIG. 9H, the flexibleregion 904 a has a length L₁ of about 7 cm. In other embodiments,however, flexible region 904 a can have a length L₁ of from about 2 cmto about 140 cm (the entire working length of the shaft 904 could begenerally flexible). In still other embodiments, the shaft 904 and/orthe flexible region 904 a can have a different arrangement and/orconfiguration.

The probe 900 can have a working or effective length L₂ of from about 55cm to about 140 cm. As used herein, “working length” and “effectivelength” are defined as the length of the probe 900 (e.g., the shaft 904,the intermediate portion 908, and the electrode 906) that will fitinside a patient's body. In configurations where a 55 cm guide catheteris used to facilitate delivery of the probe 900, the working oreffective length may be from about 60 cm to about 80 cm. Inconfigurations where a 90 cm guide catheter is used to facilitatedelivery of the probe 900, the working or effective length may be fromabout 95 cm to about 120 cm. In the illustrated embodiment, for example,the probe 900 has a working or effective length L₂ of about 108 cm andis configured for use with a sheath 910 having a length of about 90 cm.In other embodiments, however, the probe 900 can have a differentworking length L₂ and/or be configured for use with a sheath having adifferent dimension and/or configuration.

The electrode 906 includes a band 914 constructed from a first metal(e.g., platinum or iridium) and a second metal 916 disposed inside theband 914. The band 914 can be generally cylindrical or have anothersuitable shape. The second metal 916 can be the same as the first metal,or the second metal 916 can be a different metal or metal alloy. Thewires are electrically coupled to one another. For example, the wirescan be electrically connected directly or connected via the first and/orsecond metal. Thus, the electrode 906 can deliver an electric fieldsupplied from the field generator 110 via the wires 112 a-b to the wallof the body lumen. In an alternative embodiment, a single wire is usedinstead of a pair of wires.

The electrode 906 can also measure temperature (via a thermocouple orthermistor, or other temperature sensing elements), impedance or anotherparameter while delivering the electric field to the tissue. Forexample, voltage and current of the supplied electric field can bemeasured, and a resistance or impedance can be calculated according toOhm's law.

One expected advantage of an embodiment where only impedance is measuredis that only one wire is needed for the probe 900. If the probe 900includes a temperature sensor electrically connected to the electrode,then at least one more wire must be used. In this case, a total of twowires can be used to deliver energy, measure impedance and measuretemperature. If the probe 900 includes a temperature sensor electricallyindependent from the electrode then at least one more wire must be used.Additionally, more than one temperature sensors may be used to makeadditional temperature measurements. The additional wires can add to thesize and complexity of the probe 900 and increase the potential for amalfunction.

Although the illustrated electrode 906 includes the band 914, theelectrode 906 can have other configurations. For example, the electrode906 can include a coil constructed from a first metal wrapped around acore constructed from a second metal. One expected advantage of having acoil is that the coil can reduce stress due to heat expansion whenmeasuring temperature. In another embodiment, the electrode can beformed from a single metal or other conductor without the band.

FIG. 9I is an exploded view of a portion of the probe 900 taken from thearea 9I of FIG. 9H. The intermediate portion 908 may be comprised of asolid wire, ribbon, cylindrical tube, or coil constructed from stainlesssteel, nitinol, plastic or another suitable material (or combinationsthereof) that can bend or otherwise flex or be actively directed tofacilitate contact between the electrode 906 and the correspondingvessel wall. In the illustrated embodiment, the intermediate portion 908flexes or bends to locate the electrode 906 at a dimension Y from alongitudinal axis S of the shaft 904. The dimension Y can vary fromabout 2 mm to about 20 mm. In some configurations, the Y dimension canbe from about 10 mm to about 20 mm. In the illustrated embodiment, forexample, the dimension Y is about 16 mm. By way of example, the averagediameter of a human renal artery is from about 3 mm to about 8 mm.Accordingly, if the shaft 904 was positioned adjacent to a wall of anartery having an 8 mm diameter, the intermediate section 908 would haveenough flexure or arch for the electrode 906 to contact the oppositewall of the artery. In other embodiments, however, the dimension Y canhave a different value and maybe oversized to facilitate contact in astraight or curved vessel.

The intermediate portion 908 is also configured to locate the electrode906 at a dimension X from a distal portion 904 b of the shaft 904. Thedimension X can vary based, at least in part, on the material of whichthe intermediate portion 908 is composed (e.g., stainless steel ornitinol) and the desired working or effective length for the probe 900.For example, the dimension X of the intermediate portion 908 should beconfigured and sized to provide sufficient wall contact pressure suchthat the electrode 906 can create the desired treatment effect.

In alternative embodiments, a pull or push wire can be used to activelyflex the intermediate portion to facilitate placement of the electrode.For example, as illustrated in FIGS. 9L to 9N, an electrode tip 985 of aprobe 980 can be deflected or steered using an actuator wire 982. Theactuator wire 982 can be pulled from a first position or position of nodeflection 986, as shown in FIG. 9L, to a second position of slightdeflection 987, as shown in FIG. 9M, to a third position of substantialdeflection 988, as shown in FIG. 9N. The variable deflection of theprobe 980 can be particularly helpful, for example, when attempting toachieve wall contact in a curved vessel.

Referring back to FIG. 9I, the shaft 904 has an outer diameter D of fromapproximately 0.014 inches to approximately 0.085 inches. The outerdiameter D of the shaft 904 can vary based, at least in part, on theouter diameter of the electrode 906. In the illustrated embodiment, forexample, the shaft 904 has an outer diameter D of about 0.040 inches,which corresponds to one particular configuration of the electrode 906.

The electrode 906 has an outer diameter E of from about 0.020 inches toabout 0.085 inches. In the illustrated embodiment, for example, theelectrode 906 has an outer diameter E of about 0.049 inches. Thesedimensions can vary, however, from a practical standpoint, the outerdiameter E of the electrode 906 can be no bigger than the inner diameterof the sheath or guide catheter (e.g., the sheath 910) through which theelectrode 906 is delivered. In one particular example, an 8 French guidecatheter (which has an inner diameter of 0.091 inches) would likely bethe largest catheter used to access the renal artery. Thus, an electrodeused in this situation would have an outer diameter E at leastapproximately less than 0.085 inches.

In an alternative embodiment, the catheter can be configured such thatthe sheath does not cover the entire electrode, but is rather used onlyto substantially straighten the intermediate portion of the catheter tofacilitate delivery to the treatment location. In such configurations,the distal end of the sheath will abut the proximal end of theelectrode. Accordingly, it would not be necessary for the electrode sizeto be limited by the inner diameter of the sheath.

FIG. 9J is a schematic side view of an embodiment of an intravascularapparatus 950 including the probe 900 with the shaped or self-expandingelectrode 906. The electrode 906 can be delivered to a treatment sitewithin the sheath 910, and then it can move to a preselected shape afterit has been removed from the lumen of the sheath 910. For example, theelectrode 906 can be removed from the sheath 910 by advancing the shaft904 and/or retracting the shaft 904. The electrode 906 contacts thevessel wall for delivery of therapy. Optionally, the shaft 904 may berotated to rotate the electrode 906 relative to the vessel wall andangularly reposition the electrode 906. The therapy can be delivered ata singular angular position or at multiple angular positions. Infusate Ioptionally may be delivered through the sheath 910 as shown.

It should be understood that in any of the embodiments disclosed herein,a guide wire can be optionally employed to facilitate delivery and/orremoval of the probe. In such embodiments, the probe may be additionallyconfigured with structural enhancements (e.g., guide wire lumen) foraccommodating the use of a guide wire.

Additionally or alternatively, the apparatus 950 can include multipleangularly spaced electrodes 906 positioned within the vasculature, asshown in FIG. 9K. In addition to angular spacing, the electrodes 906 maybe longitudinally spaced to facilitate treatment over a longitudinalsegment of the vessel (e.g., to achieve a circumferential treatmentalong the longitudinal segment rather than along a cross-section).

In addition to extravascular and intravascular systems forthermally-induced renal neuromodulation, intra-to-extravascular systemsmay be provided. The intra-to-extravascular systems may, for example,have electrode(s) that are delivered to an intravascular position, andthen at least partially passed through/across the vessel wall to anextravascular position prior to delivery of a thermal energy field.Intra-to-extravascular positioning of the electrode(s) may place theelectrode(s) in closer proximity to target neural fibers for delivery ofa thermal energy field, as compared to fully intravascular positioningof the electrode(s). Applicants have previously describedintra-to-extravascular pulsed electric field systems, for example, inco-pending U.S. patent application Ser. No. 11/324,188, filed Dec. 29,2005, which is incorporated herein by reference in its entirety.

FIG. 10 is a schematic side view illustrating an embodiment of anintra-to-extravascular (“ITEV”) system 900 for thermally-induced renalneuromodulation. The ITEV system 900 includes a catheter 922 having (a)a plurality of proximal electrode lumens terminating at proximal sideports 924, (b) a plurality of distal electrode lumens terminating atdistal side ports 926, and (c) a guidewire lumen 923. The catheter 922preferably includes an equal number of proximal and distal electrodelumens and side ports. The ITEV system 900 also includes proximal needleelectrodes 928 that can be advanced through the proximal electrodelumens and the proximal side ports 924, as well as distal needleelectrodes 929 that may be advanced through the distal electrode lumensand the distal side ports 926. Alternatively, the embodiment illustratedin FIG. 10 can be configured with a single needle electrode configuredfor monopolar energy delivery.

The catheter 922 includes an optional expandable positioning element930. The positioning element 930 can include, for example, an inflatableballoon or an expandable basket or cage. In use, the positioning element930 may be expanded prior to deployment of the needle electrodes 928 and929 to position or center the catheter 922 within the patient's vessel(e.g., within renal artery RA). Centering the catheter 922 is expectedto facilitate delivery of all needle electrodes 928 and 929 to desireddepths within/external to the patient's vessel (e.g., to deliver all ofthe needle electrodes 928 and 929 to approximately the same depth). Inthe embodiment illustrated in FIG. 10, the positioning element 930 isbetween the proximal side ports 924 and the distal side ports 926 and,accordingly, the positioning element 930 is between the deliverypositions of the proximal and distal electrodes. However, it should beunderstood that the positioning element 930 additionally oralternatively can be positioned at a different location or at multiplelocations along the length of the catheter 922 (e.g., at a locationproximal of the side ports 924 and/or at a location distal of the sideports 926).

As shown in FIG. 10, the catheter 922 may be advanced to a treatmentsite within the patient's vasculature over a guidewire (not shown) viathe lumen 923. During intravascular delivery, the needle electrodes 928and 929 may be positioned such that their non-insulated and sharpeneddistal regions are positioned within the proximal and distal lumens,respectively. Once at a treatment site, a medical practitioner mayadvance the electrodes 928 and 929 via their proximal regions that arelocated external to the patient. Such advancement causes the distalregions of the electrodes 928 and 929 to exit side ports 924 and 926,respectively, and pierce the wall of the patient's vasculature such thatthe electrodes are positioned extravascularly via an ITEV approach.

The proximal electrodes 928 can be connected to a field generator (notshown) as active electrodes, and the distal electrodes 929 can serve asreturn electrodes. In this manner, the proximal and distal electrodes928 and 929 form bipolar electrode pairs that align the thermal energyfield with a longitudinal axis or direction of the patient'svasculature. The distal electrodes 929 alternatively may comprise theactive electrodes and the proximal electrodes 928 may comprise thereturn electrodes. Furthermore, the proximal electrodes 928 and/or thedistal electrodes 929 may both comprise active and return electrodes.Further still, the proximal electrodes 928 and/or the distal electrodes929 may be utilized in combination with an external ground for deliveryof a monopolar thermal energy field. Any combination of active anddistal electrodes may be utilized.

When the electrodes 928 and 929 are connected to a field generator andpositioned extravascularly (and with the positioning element 930optionally expanded) delivery of the thermal energy field can providethe desired renal neuromodulation via heating. After achievement of thedesired thermally-induced renal neuromodulation, the electrodes 928 and929 can be retracted within the proximal and distal lumens, and thepositioning element 930 can be collapsed for retrieval. The ITEV system900 can then be removed from the patient to complete the procedure.Additionally or alternatively, the system 900, or any system disclosedherein, may be repositioned to provide therapy at another treatmentsite, such as to provide bilateral renal neuromodulation.

Cooling elements, such as convective cooling elements, may be utilizedto protect non-target tissues like smooth muscle cells from thermalalteration during thermally-induced renal neuromodulation via heatgeneration. Non-target tissues may be protected by focusing the thermalenergy on the target neural fibers such that an intensity of the thermalenergy is insufficient to induce thermal alteration in non-targettissues distant from the target neural fibers.

Although FIGS. 3A-8B and 10 illustrate bipolar systems, it should beunderstood that monopolar systems alternatively may be utilized as shownin FIGS. 9A-9N. For example, an active monopolar electrode may bepositioned intravascularly, extravascularly, or intra-to-extravascularlyin proximity to target neural fibers that contribute to renal function.A return electrode may be attached to the exterior of the patient orpositioned in the patient apart from the active electrodes. Finally, athermal energy field may be delivered between the in vivo monopolarelectrode and the remote electrode to effectuate desiredthermally-induced renal neuromodulation. Monopolar apparatusadditionally may be utilized for bilateral renal neuromodulation.

The embodiments described above with reference to FIGS. 3A-10 aredirected generally to methods and systems for thermally-induced renalneuromodulation via delivery of thermal energy fields that modulate thetarget neural fibers. However, it should be understood that alternativemethods and systems for thermally-induced (via both heating and cooling)renal neuromodulation may be provided. For example, electric fields maybe used to cool and modulate the neural fibers with thermoelectric orPeltier elements. Also, thermally-induced renal neuromodulationoptionally may be achieved via resistive heating, via delivery of aheated or chilled fluid (see FIGS. 11 and 13), via a Peltier element(see FIG. 12), etc. Thermally-induced renal neuromodulation additionallyor alternatively may be achieved via application of high-intensityfocused ultrasound to the target neural fibers (see FIGS. 14A, 14B, and15). Additional and alternative methods and systems forthermally-induced renal neuromodulation may be used in accordance withthe present disclosure.

FIG. 11, for example, is a schematic side view of an alternativeembodiment of an apparatus 1000 for thermally-induced neuromodulationvia application of thermal energy. In this embodiment, the electrodes328 and 329 of FIG. 10 have been replaced with infusion needles 1028 and1029, respectively. A thermal fluid F may be delivered through theinfusion needles 1028 and 1029 to the target neural fibers. The thermalfluid F may be heated in order to raise the temperature of the targetneural fibers above a desired threshold. For example, the temperature ofthe neural fibers can be raised above a body temperature of about 37°C., or above a temperature of about 45° C. Alternatively, the thermalfluid F may be chilled to reduce the temperature of the target neuralfibers below a desired threshold. For example, the neural fibers can becooled to below the body temperature of about 37° C., or further cooledbelow about 20° C., or still further cooled below a freezing temperatureof about 0° C. As will be apparent, in addition tointra-to-extravascular delivery of a thermal fluid, the thermal fluid Fmay be delivered intravascularly (e.g., may inflate and/or be circulatedthrough a balloon member), extravascularly (e.g., may be circulatedthrough a vascular cuff), or a combination thereof.

In addition or as alternative to injection of a thermal fluid to thetarget neural fibers through infusion needles 1028 and 1029, analternative neuromodulatory agent, such as a drug or medicament, may beinjected to modulate, necrose or otherwise block or reduce transmissionalong the target neural fibers. Examples of alternative neuromodulatoryagents include, but are not limited to, phenol and neurotoxins, such asbotulinum toxin. Additional neuromodulatory agents, per se known, willbe apparent to those of skill in the art.

FIG. 12 is a schematic side view illustrating still another embodimentof an apparatus 1100 for thermal renal neuromodulation via applicationof thermal energy to the target neural fibers. The apparatus 1100includes a renal artery cuff 1102 having one or more integratedthermoelectric elements that are electrically coupled to an internal orexternal power supply 1104. The thermoelectric element(s) utilize thewell-known Peltier effect (i.e., the establishment of a thermal gradientinduced by an electric voltage) to achieve thermal renalneuromodulation.

An electric current is passed from the power supply 1104 to thethermoelectric element of the cuff 1102. The thermoelectric element caninclude two different metals (e.g., a p-type and an n-typesemiconductor) that are connected to each other at two junctions. Thecurrent induces a thermal gradient between the two junctions, such thatone junction cools while the other is heated. Reversal of the polarityof the voltage applied across the two junctions reverses the directionof the thermal gradient. Either the hot side or the cold side of thethermoelectric element faces radially inward in order to heat or cool,respectively, the target neural fibers that travel along the renalartery to achieve thermal renal neuromodulation. Optionally, theradially outward surface of the thermoelectric element may be insulatedto reduce a risk of thermal alteration to the non-target tissues. Thecuff 1102 may include one or more temperature sensors, such asthermocouples, for monitoring the temperature of the target neuralfibers and/or of the non-target tissues, wherein the monitored data maybe used as feedback to control the delivery of therapy.

FIG. 13 illustrates yet another embodiment of an apparatus 1200utilizing the Peltier effect. The apparatus 1200 includes an implantedor external pump 1202 connected to a renal artery cuff 1204 via an inletfluid conduit 1206 a and an outlet fluid conduit 1206 b. The inlet fluidconduit 1206 a transfers fluid from the pump 1202 to the cuff 1204,while the outlet fluid conduit 1206 b transfers fluid from the cuff 1204to the pump 1202 to circulate the fluid through the cuff 1204. Areservoir of fluid may be located in the cuff 1204, the pump 1202,and/or in the fluid conduits 1206 a and 1206 b.

The pump 1202 can further include one or more thermoelectric or otherthermal elements in heat exchange contact with the fluid reservoir forcooling or heating the fluid that is transferred to the cuff 1204 tothermally modulate the target neural fibers. The apparatus 1200optionally may have controls for automatic or manual control of fluidheating or cooling, as well as fluid circulation within the cuff 1204.Furthermore, the apparatus 1200 may include a temperature and/or renalsympathetic neural activity monitoring or feedback control. Although theapparatus 1200 of FIG. 13 is shown unilaterally treating neural fibersinnervating a single kidney, it should be understood that bilateraltreatment of neural fibers innervating both kidneys alternatively may beprovided.

Thermal renal neuromodulation alternatively may be achieved via pulsedor continuous high-intensity focused ultrasound. Furthermore, theultrasound may be delivered over a full 360° (e.g. when deliveredintravascularly) or over a radial segment of less than 360° (e.g., whendelivered intravascularly, extravascularly, intra-to-extravascularly, ora combination thereof).

FIGS. 14A and 14B, for example, are schematic side views illustrating anembodiment of an ultrasonic apparatus 1300 including a catheter 1302,one or more ultrasound transducers 1304 positioned along the shaft ofthe catheter 1302, and an inflatable balloon 1306 around the transducers1304. FIG. 14A illustrates the apparatus 1300 in a reduced delivery andretrieval configuration, and FIG. 14B illustrates the apparatus 1300 inan expanded deployed configuration. The ultrasound transducers 1304 arecoupled to an ultrasound signal generator (not shown) via conductors1307. The balloon 1306 can have an acoustically reflective portion 1308for reflecting an ultrasound wave and an acoustically transmissiveportion 1309 through which the ultrasonic energy can pass. In thismanner, the wave may be focused as shown at a focal point or radius Ppositioned a desired focal distance from the catheter shaft. In analternative embodiment, the transducers 1304 may be attached directly tothe balloon 1306.

The focal distance may be specified or dynamically variable such thatthe ultrasonic wave is focused at a desired depth on target neuralfibers outside of the vessel. For example, a family of catheter sizesmay be provided to allow for a range of specified focal distances. Adynamically variable focal distance may be achieved, for example, viacalibrated expansion of the balloon 1306.

Focusing the ultrasound wave may produce a reverse thermal gradient thatprotects the non-target tissues and selectively affect the target neuralfibers to achieve thermal renal neuromodulation via heating. As aresult, the temperature at the vessel wall may be less than thetemperature at the target tissue.

FIG. 15 illustrates still another embodiment of an ultrasonic apparatus1400 having a catheter 1402, a conductor 1403, and concave ultrasoundtransducers 1404. The concave ultrasound transducers 1404 direct theenergy to a specific focal point P. As such, the concave transducers1404 are self-focusing and eliminate the need for reflective portions onthe balloon 1406 (e.g., the balloon may be acoustically transmissive atall points).

The systems described above with respect to FIGS. 3A-15 optionally maybe used to quantify the efficacy, extent, or cell selectivity ofthermally-induced renal neuromodulation in order to monitor and/orcontrol the neuromodulation. As discussed previously, the systems canfurther include one or more sensors, such as thermocouples or imagingtransducers, for measuring and monitoring one or more parameters of (a)the system, (b) target neural fibers, and/or (c) non-target tissues. Forexample, a temperature rise or drop above or below certain thresholds isexpected to thermally ablate, non-ablatively alter, freeze, or otherwisealter the target neural fibers to thereby modulate the target neuralfibers.

It should be understood that any of the methods, apparatuses, andsystems disclosed herein can be modified or configured for cooling orfreezing treatments which modulate neural fibers. For example, any ofthe probes disclosed herein can be modified to deliver cryotherapy tothe target neural fibers with either an intravascular, extravascular orITEV approach.

D. Modules and Methods for Controlling Thermally-Induced RenalNeuromodulation

With the treatments disclosed herein for delivering therapy to targettissue, it may be beneficial for energy to be delivered to the targetneural structures in a controlled manner. The controlled delivery ofenergy will allow the zone of thermal treatment to extend into the renalfascia while minimizing undesirable energy delivery or thermal effectsto the vessel wall. A controlled delivery of energy may also result in amore consistent, predictable and efficient overall treatment.Accordingly, it may be beneficial to incorporate a controller orcomputer system having programmed instructions for delivering energy totissue into the energy delivery system. Additionally, these programmedinstructions may comprise an algorithm for automating the controlleddelivery of energy. Alternatively, the delivery of energy to targettissue can be controlled manually by an operator or the physicianadministering treatment.

In one embodiment, for example, a controller can command a powergenerator (e.g., the field generator 110 of FIGS. 3A and 3B) inaccordance with an algorithm comprising various power delivery profiles.FIG. 16, for example, is a flow chart illustrating a method 1600 ofcontrolling such power delivery processes. The method 1600 can beimplemented as a conventional computer program for execution by theprocessor 114 of FIG. 3A or another suitable device (e.g., the fieldgenerator 110). The method 1600 can also be implemented manually by anoperator.

As illustrated in FIG. 16, after treatment is initiated, the first stage1602 of the method 1600 includes monitoring certain operating parameters(e.g., temperature, time, impedance, power, etc.). While it is preferredthat these operating parameters are monitored continuously, they canalternatively be monitored periodically. At stage 1604, the method 1600includes checking the monitored parameters against predeterminedparameter profiles to determine whether the parameters individually orin combination fall within the ranges set by the predetermined parameterprofiles. For example, temperature can be monitored and compared to apredetermined temperature value. Alternatively, both temperature andimpedance can be monitored and compared to a predetermined parameterprofile of both temperature and impedance. If the monitored parametersfall within the ranges set by the predetermined parameter profiles, thentreatment is continued at the same settings and the operating parameterscontinue to be monitored.

When it is determined that one or more parameters or multiple parametersin combination fall outside a predetermined parameter profile, then themethod 1600 calls for an adjustment to the system's power output atstage 1606. The direction (i.e., increase or decrease) and degree of thepower output adjustment can be determined by a routine utilizing themonitored parameters and how they compare against other predeterminedparameter profiles. For example, if temperature and time are monitoredand it is determined that the monitored temperature and time exceed apredetermined parameter profile of temperature and time, then powerdelivery may be reduced. Alternatively, if one or more monitoredparameters or multiple monitored parameters in combination falls shortof a predetermined parameter profile, then power delivery may beincreased. As shown in FIG. 16, treatment will continue until powerdelivery has been adjusted to a level of zero (stage 1608).

The operating parameters monitored in accordance with the algorithm mayinclude temperature, time, impedance, and power. Discrete values intemperature may be used to trigger changes in energy delivery. Forexample, high values in temperature (e.g. 85° C.) could indicate tissuedesiccation in which case the algorithm may decrease or stop the energydelivery to prevent undesirable thermal effects to target or non-targettissue. Time may also be used to prevent undesirable thermal alterationto non-target tissue. For each treatment, a set time (e.g., 2 minutes)is checked to prevent indefinite delivery of energy. Impedance may beused to measure tissue changes. Impedance indicates the electricalproperty of the treatment site. If a thermal inductive, electric fieldis applied to the treatment site the impedance will decrease as thetissue cells become less resistive to current flow. If too much energyis applied, tissue desiccation or coagulation may occur near theelectrode which would increase the impedance as the cells lose waterretention and/or the electrode surface area decreases (e.g., via theaccumulation of coagulum). Thus, an increase in tissue impedance may beindicative or predictive of undesirable thermal alteration to target ornon-target tissue. Additionally, power is an effective parameter tomonitor in controlling the delivery of therapy. Power is a function ofvoltage and current. The algorithm may tailor the voltage and/or currentto achieve a desired power. Derivatives of the aforementioned parameters(e.g., rates of change) can also be used to trigger change in energydelivery. For example, the rate of change in temperature could bemonitored such that power output is reduced in the event that a suddenrise in temperature is detected.

To implement the aforementioned control algorithm, the system mayinclude one or more computing system hardware and/or software modules.Alternatively, computer hardware and software can be utilized tofacilitate any energy delivery process or system. FIG. 17, for example,illustrates a functional diagram showing software modules 1620 suitablefor use in the processor 114 of FIG. 3A or another suitable device(e.g., the field generator 110) to perform methods for modulating renalnerves. Each component can be a computer program, procedure, or processwritten as source code in a conventional programming language, such asthe C++ programming language, and can be presented for execution by theCPU of processor 114. The various implementations of the source code andobject and byte codes can be stored on a computer-readable storagemedium or embodied on a transmission medium in a carrier wave. Themodules of the processor 114 can include an input module 1622, adatabase module 1624, a process module 1626, an output module 1628, anda display module 1630. In another embodiment, the software modules 1620can be presented for execution by the CPU of a network server in adistributed computing scheme.

In operation, the input module 1622 accepts operator input, such asprocess setpoint and control selections, and communicates the acceptedinformation or selections to other components for further processing.The database module 1624 organizes records, including an operatingparameter 1634, an operator activity 1636, and one or more alarms 1638,and the database module 1624 facilitates storing and retrieving of theserecords to and from a database 1632. Any type of database organizationcan be utilized, including a flat file system, hierarchical database,relational database, or distributed database, such as those provided byOracle Corporation of Redwood Shores, Calif.

The process module 1626 can process the sensor readings 1640 (e.g., fromthe sensors 310 in FIG. 5A), check for alarms and interlocks, andgenerate control variables for controlling an energy delivery process ofthe field generator 110 (FIG. 3A) based on the sensor readings 1640. Theoutput module 1628 can generate output signals 1642 based on the controlvariables. For example, the output module 1628 can convert the generatedcontrol variables from the process module 1626 into output signals 1642suitable for an energy output modulator. The display module 1630 candisplay, print, or download the sensor readings 1640 and the outputsignals 1642 via devices such as the output device 120 (FIG. 3A) or avisual display on the face of the field generator 110. A suitabledisplay module 1630 can be a video driver that enables the processor 114to display the sensor readings 1640 on the output device 120.

FIG. 18 is a block diagram showing an embodiment of the process module1626 of FIG. 17. The process module 1626 can further include a sensingmodule 1650, a calculation module 1652, an alarm module 1654, a poweroutput module 1656, and an interlock module 1658 interconnected witheach other. Each module can be a computer program, procedure, or routinewritten as source code in a conventional programming language, or one ormore modules can be hardware modules.

The sensing module 1650 can receive and convert the sensor readings 1640into parameters in desired units. For example, the sensing module 1650can receive the sensor readings 1640 as electrical signals and convertthe electrical signals into instant temperatures in Celsius. The sensingmodule 1650 can have routines including, for example, linearinterpolation, logarithmic interpolation, data mapping, or otherroutines to associate the sensor readings 1640 to parameters in desiredunits.

The calculation module 1652 can perform various types of calculation tofacilitate operation of other modules. For example, the calculationmodule 1652 can derive an average temperature based on the measuredtemperatures over a period of time according to the following formula:

$T_{avg} = \frac{\Sigma \; T_{i}}{N}$

where T_(i) is a measured temperature, T_(avg) is the averagetemperature, and N is the number of temperature records. Other averagingtechniques, such as an exponential moving average can also be used. Thecalculation module 466 can also derive a rate of change for the measuredtemperature according to the following formula:

$\frac{T}{t} \approx \frac{T_{i + 1} - T_{i}}{\Delta \; t}$

where T_(i+1) is the temperature record number i+1, T_(i) is theprevious temperature record, and Δt is the time difference between thetwo temperature records.

The alarm module 1654 can generate alarms based on output from thecalculation module 1652 and/or the sensing module 1650. For example, thealarm module 1654 can compare the average or instantaneous temperaturecalculated in the calculation module 1652 to a preset threshold value(i.e., predetermined parameter profile). If the average or instantaneoustemperature exceeds the threshold value, the alarm module 1654 can issuean alarm by raising an alarm flag or another type of response. Inresponse to the alarm flag, the output device 120 (FIG. 3A) can issue anotification by displaying a flashing message, sounding a horn, turningon a warning light, and/or providing another indicator. In certainembodiments, the alarm module 1654 can also include routines forimplementing hysteresis. For example, the alarm module 1654 can latchthe alarm flag when the average or instantaneous temperature exceeds thethreshold and deactivate the alarm only when the average orinstantaneous temperature drops below the threshold by a certain amount.

The power output module 1656 can generate the output signals 1642 to thefield generator 110 (FIGS. 3A and 3B) for modulating power output of thefield generator 110. In one embodiment, the power output module 1656 cangenerate the output signals 1642 according to a preset power deliveryprofile. For example, the power delivery profile can include a maximumpower level, a minimum power level, and a rate of increase over acertain period of time to ramp from the minimum power level to themaximum power level. In other embodiments, the power output module 1656can generate the output signals 1642 based on monitored operatingparameter data or other output from the sensing module 1650 and/or thecalculation module 1652. For example, the power output module 1656 canmodify the rate of increase based on the average temperature calculatedin the calculation module 1652, or the instant temperature from thesensing module 1650, as described below.

The interlock module 1658 continuously monitors operating parametersreceived from the sensing module 1650 and/or the calculation module1652, and the interlock module 1658 can control operation of the poweroutput module 1656 when the monitored operating parameters exceedcertain interlock threshold values. Depending on the interlockcondition, the power output module 1656 can set a power setpoint aboveor below the current setpoint (i.e., increase or decrease power) or itcan set a power setpoint of zero (i.e., terminate power delivery). Forexample, the interlock module 1658 can cause the power output module1656 to reduce the power output when the average temperature from thecalculation module 1652 exceeds a preset value. Additionally oralternatively, the interlock module can cause the power output module1656 to terminate its operation (i.e., having a zero output value) whenthe instant temperature from the sensing module 1650 exceeds anotherpreset value. In several embodiments, the interlock module 1658 canoptionally be configured to directly generate output signals 1642 to theother system components.

In certain embodiments, the process module 1626 can include additionalmodules. For example, the process module 1626 can include aconfiguration module for configuring any one of the sensing module 1650,the calculation module 1652, the alarm module 1654, the power outputmodule 1656, and/or the interlock module 1658.

The process module 1626 can also include control modules for controllingselected process parameters. For example, the process module 1626 caninclude proportional-integral-derivative (PID) modules for maintaining aprocess parameter (e.g., the measured temperature) at a desired value.The process module 1626 can also include one or more PID modules thatattempt to maintain one process parameter (e.g., temperature) unlesslimited by other process parameters (e.g., maximum power or impedancevalues). The process module 1626 can also include feed-forward modulesin addition to the PID modules for improved control. For example, thefeed-forward modules can calculate an expected power level based on themeasured temperature, the heat conductance, and/or other parameters ofthe wall of the body lumen. The expected power level can then becombined with the output of the PID modules to compensate for anydelayed response.

To better understand the methods described above with reference to FIG.16, it may be helpful to discuss the method 1600 in view of a powerdelivery profile. FIG. 19, for example, is a graph of power versus timeshowing a typical response of performing an embodiment of the method1600. Referring to FIGS. 16-19 together, one embodiment of the method1600 includes a function in which the interlock module 1658 checks forinterlock conditions (i.e., monitored operating parameters vs.predetermined parameter profiles), which corresponds to stages 1602 and1604 of FIG. 16. If any interlock condition exists, then at stage 1606the interlock module 1658 adjusts power output or delivery (e.g.,increase/decrease power level or force output to zero). If it isdetermined that the power level is adjusted to zero at stage 1608, thetherapy is terminated. The interlock conditions can include thoseindicating an unsafe or undesired operating state, or those indicatingincomplete energy delivery. For example, the following is anon-exhaustive list of events that can be the interlock conditions:

-   -   (1) The measured temperature exceeds a maximum temperature        threshold (e.g., about 70° to about 85° C.).    -   (2) The average temperature derived from the measured        temperature exceeds an average temperature threshold (e.g.,        about 65° C.).    -   (3) The rate of change of the measured temperature exceeds a        rate of change threshold.    -   (4) The temperature rise over a period of time is below a        minimum temperature change threshold while the field generator        110 (FIG. 3A) has non-zero output. Poor contact between the        electrode 108 and the wall can cause such a condition.    -   (5) A measured impedance exceeds an impedance threshold (e.g.,        <20 Ohms, or >500 Ohms).    -   (6) A measured impedance exceeds a relative threshold (e.g.,        impedance decreases from a starting or baseline value and then        rises above this baseline value).

As illustrated in FIG. 19, the first interlock condition occurs at time0 (i.e., the time at which the operator has initiated treatment and thetimer begins counting up from zero). In this case, the method 1600continues at stage 1606 with the power output module 1656 commanding thefield generator 110 to gradually adjust its power output to a firstpower level P₁ (e.g., 5 watts) over a first time period (0−t₁) (e.g., 15seconds). The power output module 470 can generate and transmit a powersetpoint to the field generator 110 as the output signals 1642. In oneembodiment, as illustrated in FIG. 19, the power increase during thefirst time period is generally linear. As a result, the field generator110 increases its power output at a generally constant rate of P₁/t₁. Inother embodiments, the power increase can be non-linear (e.g.,exponential or parabolic) with a variable rate of increase.

After the first time period expires (or after the power level at P, hasbeen achieved), the power output module 1656 can command the fieldgenerator 110 to maintain its current output power level at P₁, i.e.,pause for a second time period (t₁−t₂). An operator or preprogrammedroutine can adjust the time period (t₁−t₂) based on the patient'sphysiological characteristics. For example, if the patient's body lumenis slow in responding to temperature changes, then the operator orpreprogrammed routine can increase the time period (t₁−t₂) to compensatefor the additional response delay. In other embodiments, the poweroutput module 1656 may cause the field generator 110 to reduce theoutput level to less than P₁ or momentarily terminate its output levelduring the second time period (t₁−t₂) or any other time period (e.g.,the first time period or subsequent time periods).

After the second time period expires, the calculation module 1652 canderive an average temperature at the end of the second time period,i.e., t₂, based on the temperature from the sensing module 1650. Themethod 1600 can continue with a test to determine whether the calculatedaverage temperature at t₂ exceeds a preset threshold (e.g., 65° C.). Ifthe average temperature exceeds the preset threshold, then the poweroutput module 1656 can command the field generator 110 to maintain itscurrent output power level for a desired total treatment time.

If the average temperature does not exceed the preset threshold, thenthe method 1600 can continue at stage 1606 with the power level P_(i)being increased by an amount ΔP from P_(i). In one embodiment, ΔP can bea predetermined fixed amount (e.g., 0.5 watts). In other embodiments, ΔPcan be a variable amount. For example, the difference between theaverage temperature and a maximum temperature threshold can determine ΔPaccording to the following formula:

ΔP=k×(T _(max) −T _(avg))

where k is a user-selected or predetermined constant, T_(max) is themaximum temperature threshold, and T_(avg) is the average temperature.

The method 1600 can continue with another test to determine whether theincreased power level (P_(i)+ΔP) exceeds a maximum power level (e.g., 10watts) for the field generator 110. An operator or preprogrammed routinecan select the maximum power level to represent a safe or preferredoperating mode and adjust the selected power level based on treatmentconditions. If the maximum power level is exceeded, then power outputmodule 1656 commands the field generator 110 to maintain its currentoutput power level until a desired total treatment time is reached. Ifthe maximum power level is not exceeded, then the process returns topausing, and the subsequent stages are repeated. Although the specificexample of the method 1600 described above uses the measured temperatureas a process parameter, other physiological parameters (e.g., impedance,resistivity, and/or capacitance) and non-physiological parameters (e.g.,time, power, etc.) can be used instead of or in addition to the measuredtemperature.

Optionally, the calculation module 1652 can calculate the number ofcycles before the maximum power level is reached. For example, when afixed ΔP is used, the calculation module 1652 can calculate the numberof cycles according to the following formula:

$n = \frac{P_{\max} - P_{1}}{\Delta \; P}$

where P_(max) is the maximum power level, and n is the number of cycles.

After the ramp up process terminates, the power output module 1656 canstill command the field generator 110 to modify its power output levelbased on the calculated average temperature, the rate of change of themeasured temperature, the rate of change in impedance, and/or otherparameters. For example, as discussed below, the power output module1656 can command the field generator 110 to discretely or continuouslydecrease its power output level when the measured temperature isincreasing at a rate exceeding a rate of change threshold or when themeasured instant temperature exceeds another preset threshold.

The method 1600 can also optionally include a ramping process thatallows the power level to be increased at a faster rate. For example,the method 1600 can include a test to check the average temperature anddetermine if it is below a preselected threshold (e.g., 50 C). If theaverage temperature is below the threshold, then the power output module1656 can command the field generator 110 to increase the power levelP_(i) by an amount equal to ΔP×F where F is a step factor (e.g., 2). Thetest can be repeated at the start of each ramp stage or at otherselected points in the ramping process. The rapid ramping process isexpected to allow the power output level to reach its desired treatmentlevel more quickly. In another embodiment where a PID module is used tocontrol power output, the PID module can be tuned to rapidly ramp uppower when the measured temperature is far below a specified level(e.g., 65 C) but slow down the power ramping as the measured temperatureapproaches the specified level.

The method 1600 can also optionally include a power reduction process toincrementally step down or ramp down the power level during treatment.The example described above specifically tailors the power outputprocess to reduce the risk of overheating the walls of the patient'sbody lumen via temperature monitoring. In the case where the maximumpower level is reached, the temperature and/or the measured impedancemay continue to rise beyond a certain threshold. In many cases,exceeding such thresholds could be an indicator that an alarm thresholdcould be reached where power output would be terminated. The methoddescribed below, however, can be used to decrease power to prevent apremature termination of power delivery due to temperature and/orimpedance reaching an alarm threshold.

During power delivery, the interlock module 1658 can continuouslymonitor one or more operating parameters received from the sensingmodule 1650 and/or the calculation module 1652. For example, this methodcan include a test to determine whether the calculated averagetemperature is greater than or equal to a preset threshold T_(t) (e.g.,70° C.). If the average temperature does not exceed the preset thresholdT_(t), then the interlock module 1658 does not interrupt operation ofthe power output module 1656 and the current power output level ismaintained for treatment.

On the other hand, if the average temperature (from the calculationmodule 1652) exceeds the preset threshold T_(t), then the method cancontinue with stage 1606 in which the power level is reduced. Duringthis power reduction stage, the power output module 1656 can command thefield generator to immediately decrease power by P_(s) (e.g., 1 watt).After decreasing the power, the method can pause the power output module1656 for a time period T_(w) (e.g., 3 seconds). After the time periodT_(w) expires, the calculation module 1652 can again derive an averagetemperature based on the temperature from the sensing module 1650. Themethod can continue with another test at to determine whether thecalculated average temperature still exceeds the preset threshold T_(t).In some cases, this power reduction process may need to be repeatedseveral times, decreasing power by P_(s) each time, until the averagetemperature does not exceed the preset threshold. If the averagetemperature does not exceed the threshold, the method can continue witha sustained power stage for the duration of the treatment time.

In another aspect of this embodiment, the method can include a test todetermine whether an increase or rate of increase in impedance is toolarge. More specifically, the interlock module 1658 can measure theslope of the impedance over a fixed period of time. If the measuredslope does not exceed a preset threshold, then the interlock module 1658does not adjust operation of the power output module 1656, and themethod can continue with a sustained power level. However, if themeasured slope is greater than a preset threshold Z_(s) (e.g., 3 ohmsper second), then the method can proceed to the power reductiondescribed above. As mentioned above, the power reduction process mayneed to be repeated several times until the measured slope does notexceed the preset threshold Z_(s). An operator or preprogrammed routinecan adjust the preset thresholds T_(t) and Z_(s) or the power reductionrate based on the patient's physiological characteristics and/or one ormore desired treatment parameters.

In yet another aspect of this embodiment, the interlock module 1658 cancontinuously monitor the impedance and, if at any point during treatmentthe impedance rises above a minimum impedance plus a preselectedthreshold, the power output can be decreased until the impedance valueis within the desired range. If the impedance value does not change tobe within the desired range or continues to rise above an alarmthreshold, then power delivery can be terminated.

In further detail, this method can include a test to compare themeasured impedance value with a preselected minimum impedance value. Ifthe measured impedance value is less than the preselected minimumimpedance value, the minimum value is updated to be equal to themeasured value. These stages can be repeated any number of times asnecessary during treatment. In effect, the method keeps track of thelowest impedance value measured by the system.

If the measured impedance is greater than the minimum impedance valueplus a preselected threshold value Z_(d) (e.g., 20 ohms), then themethod can continue to the power reduction process as described above.After decreasing the power, the method can pause the power output module1656 for a time period T_(w2) (e.g., 3 seconds). After the time periodT_(w2) expires, the interlock module 1658 can again monitor impedanceand, if the measured impedance value is still greater than the minimumimpedance value plus the threshold value, the method can repeat thepower reduction process any number of times as necessary until theimpedance condition does not occur, and then return to the sustainedpower stage.

One expected advantage of the methods 1600 and the various embodimentsdescribed above is the reduced risk of undesirable treatment effects totarget and non-target tissue (e.g., excessively damaging the wall of thebody lumen). As described above with reference to FIGS. 3A and 3B, thefield generator 110 can deliver an electric field to the probe 104 toapply energy to the wall of the body lumen and surrounding areas foreffectuating neural modulation. However, many factors can contribute toa delayed response of the body lumen to the applied energy (as indicatedby the measured temperature and/or impedance). For example, the latentheat of the body lumen, circulation around or within the body lumen,contact between a sensor and the wall of the body lumen, and otherfactors can cause the delayed temperature and/or impedance response tothe applied energy. To compensate for this delay in response, the method1600 may incorporate a delay period in which some parameters are notmonitored for the duration of the delay period. As a result, adverseoverheating of the body lumen can be mitigated or even eliminated.Furthermore, a power reduction process further helps reduce the risk ofexcessively damaging the body lumen wall, while also preventingpremature termination of power delivery due to a parameter reaching analarm threshold.

It is expected that thermally-induced renal neuromodulation, whetherdelivered extravascularly, intravascularly, intra-to-extravascularly ora combination thereof, may alleviate clinical symptoms of CHF,hypertension, renal disease, myocardial infarction, atrial fibrillation,contrast nephropathy and/or other renal or cardio-renal diseases for aperiod of months (potentially up to six months or more). This timeperiod may be sufficient to allow the body to heal; for example, thisperiod may reduce the risk of CHF onset after an acute myocardialinfarction to thereby alleviate a need for subsequent re-treatment.Alternatively, as symptoms reoccur, or at regularly scheduled intervals,the patient may receive repeat therapy. Thermally-induced renalneuromodulation also may systemically reduce sympathetic tone.

While the therapies disclosed herein relate to modulating nerves thatcontribute to renal function via denervation, it should be understoodthat the methods, apparatuses, and systems disclosed herein can beconfigured and/or modified for therapeutic energy transfer with otherlocations within the body. For example, these inventions can be modifiedfor the purposes of energy delivery within a body lumen (e.g., aperipheral blood vessel) to achieve denervation or some othertherapeutic result.

From the foregoing, it will be appreciated that specific embodiments ofthe invention have been described herein for purposes of illustration,but well-known structures and functions have not been shown or describedin detail to avoid unnecessarily obscuring the description of theembodiments of the invention. Where the context permits, singular orplural terms may also include the plural or singular term, respectively.Moreover, unless the word “or” is expressly limited to mean only asingle item exclusive from the other items in reference to a list of twoor more items, then the use of “or” in such a list is to be interpretedas including (a) any single item in the list, (b) all of the items inthe list, or (c) any combination of the items in the list. Additionally,the term “comprising” is used throughout to mean including at least therecited feature(s) such that any greater number of the same featureand/or additional types of other features are not precluded. It willalso be appreciated that specific embodiments have been described hereinfor purposes of illustration, but that various modifications may be madewithout deviating from the invention. Accordingly, the invention is notlimited except as by the appended claims.

1-117. (canceled)
 118. A field generator adapted to be external to ahuman patient and operably coupled to an intravascular catheter having adistal electrode for treatment of the patient, the field generatorcomprising: non-transitory memory storing a set of instructions; and aprocessor coupled to the non-transitory memory, wherein the set ofinstructions are configured to cause the processor to— increase energydelivery, from the field generator to the electrode when the electrodeis positioned at a target intravascular site, at a generally constantrate to a predetermined first power level over a predetermined firstperiod of time; maintain energy delivery to the electrode at the firstpower level for a second period of time; and increase energy delivery tothe electrode in predetermined increments following the second period oftime if a measured temperature value at the target intravascular site isless than a preset temperature threshold and a measured impedance valueis less than a predetermined impedance threshold, the increase in energydelivery following the second period of time continuing until the powerlevel has reached a target maximum power threshold.
 119. The fieldgenerator of claim 118 wherein the set of instructions are furtherconfigured to cause the processor to maintain energy delivery at thepredetermined first power level if the measured temperature value isgreater than or equal to the preset threshold temperature.
 120. Thefield generator of claim 118 wherein the preset threshold temperature isfrom about 45 degrees Celsius to about 90 degrees Celsius.
 121. Thefield generator of claim 118 wherein the preset threshold temperature isfrom about 60 degrees Celsius to about 75 degrees Celsius.
 122. Thefield generator of claim 118 wherein the preset threshold temperature isabout 65 degrees Celsius.
 123. The field generator of claim 118 whereinthe predetermined first power level is about 5 watts.
 124. The fieldgenerator of claim 118 wherein the first period of time is about 15seconds.
 125. The field generator of claim 118 wherein the second periodof time is at least 3 seconds.
 126. The field generator of claim 118 thesecond power level is about 6 watts.
 127. The field generator of claim118 wherein the second power level is about 8 watts.
 128. The fieldgenerator of claim 118 wherein the reduction in power occurs inincrements.
 129. The field generator of claim 118 wherein the targetmaximum power threshold is a second power level, and wherein the set ofinstructions are further configured to cause the processor to reduceenergy delivery to the electrode positioned at the target intravascularsite to a third power level less than the second power level if thetemperature value reaches a second threshold temperature.
 130. The fieldgenerator of claim 129 wherein the second threshold temperature is about70 degrees Celsius.
 131. The field generator of claim 118 wherein theset of instructions are further configured to cause the processor toterminate energy delivery if an interlock condition is satisfied. 132.The field generator of claim 131 wherein the interlock condition issatisfied when the temperature value reaches a maximum thresholdtemperature.
 133. The field generator of claim 132 wherein the maximumthreshold temperature is an average temperature or real time temperaturefrom about 70 degrees Celsius to about 85 degrees Celsius.
 134. Thefield generator of claim 132 wherein the maximum threshold temperatureis an average temperature or real time temperature of about 85 degreesCelsius.
 135. The field generator of claim 132 wherein the maximumthreshold temperature is a rate of change threshold.
 136. The fieldgenerator of claim 131 wherein the interlock condition is satisfied whenthe measured impedance reaches the predetermined impedance threshold.137. The field generator of claim 136 wherein the impedance threshold isa measured impedance below about 20 Ohms or above about 500 Ohms. 138.The field generator of claim 137 wherein the impedance threshold is arelative threshold.
 139. The field generator of claim 131, furthercomprising a module for measuring a treatment time beginning when energydelivery commences, and wherein the interlock condition is satisfiedwhen the treatment time reaches a maximum procedure time.
 140. The fieldgenerator of claim 139 wherein the maximum procedure time is about 2minutes.
 141. The field generator of claim 118 wherein the set ofinstructions are further configured to cause the processor to preventpower from exceeding the target maximum power level.
 142. The fieldgenerator of claim 141 wherein the target maximum power level is fromabout 8 watts to about 10 watts.
 143. The field generator of claim 141wherein the target maximum power level is greater than about 10 watts.